Genetic Analysis of Systemic Lupus Frythematosus The single factor most dramatically increasing risk of the autoimmune disease systemic lupus erythematosus (SLE) is family history of the disease: concordance among monozygotic twins is about 70% and more than 10% of SLE patients have at least one affected relative. SLE susceptibility is also associated with HLA and immunoglobulin. However, SLE genetics is complex: more than one locus appears to be involved; the disease is probably genetically heterogeneous; and penetrance is incomplete, with expression affected by other endogenous factors or environmental exposures. Among the genes most likely to influence susceptibility to SlE are those controlling immune response. ln the course of this Program Project, probes have been characterized and polymorphisms developed in alpha, bets, and gamma chains of the T-cell receptor; heavy, light, constant, and variable chains of immunoglobulin; alpha, beta, and gamma interferons; and Leu-2. We propose a two-part genetic analysis to determine whether inherited variants in these and related sequences influence susceptibility to SLE. (1) In extended families of SLE probands, we will test for genetic linkage to DNA polymorphisms in there immune response sequences to autoimmune conditions. Segregation of a major gene for autoimmunity will be tested in a series of families selection with rigorous ascertainment criteria. Linkage will be studied in informative families. (2) A series of 100 female SLE patients of European ancestry will be compared to female controls matched on age and ancestry with respect to DNA polymorphisms in the immune response sequences. Genotypes will be compared for the entire series of casts and controls and after stratification of SLE by the presence of specific autoantibodies and clinical features, and by HLA DR type. Epidemiologic information will ba collected to assess possible influences of other endogenous factors and reproductive history on expression of SLE.